Heterocyclic compounds and compositions having nevropharmacological potential

ABSTRACT

Novel heterocyclic compounds having a structure according to general formula (1), pharmaceutically acceptable acid addition salts and solvates thereof are described as having a pharmacological profile showing potential for treatment of acute and chronic neuropsychiatric disorders which are known as progressively deteriorating conditions leading to neuronal cell death and dysfunction. Pharmaceutical formulations are described as containing said therapeutic compounds.

NEW COMPOUNDS

This is a 371 of PCT/SE94/00664 filed Jul. 5, 1994.

NEW COMPOUNDS

This is a 371 of PCT/SE94/00664 filed Jul. 5, 1994.

FIELD OF THE INVENTION

The present invention relates to novel heterocyclic compounds havingtherapeutic activity, processes and intermediates for their preparation,pharmaceutical formulations containing said compounds and the medicinaluse of said compounds.

BACKGROUND OF THE INVENTION

There exists a large group of acute and chronic neuropsychiatricdisorders for which safe and clinically effective treatments are notcurrently available. This diverse group of disorders encompasses a broadspectrum of initial events which are characterised by the initiation ofprogressive processes that sooner or later lead to neuronal cell deathand dysfunction. Stroke, cerebral ischaemia, trauma or aneurodegenerative disease such as Alzheimer's disease or Parkinson'sdisease are all commonly occurring conditions that are associated withneurodegeneration of the brain and/or spinal cord.

The ongoing search for potential treatments of neurodegenerativedisorders has involved investigation of excitatory amino acidantagonists, inhibitors of lipid peroxidation, calcium channelantagonists, inhibitors of specific pathways of the arachidonic acidcascade, kappa opioid agonists, adenosine agonists, PAF antagonists anddiverse other agents. At the present time there is no consensus of therelative importance of the role played by compounds belonging to any ofthese general classes.

In a paper on the thermal and photochemical isomerisations ofisoxazoles, A. Padwa et al (J. Amer. Chem. Soc., 1975, 97, 6484-6491)describe methylphenyl(2-phenyl-5-methyloxazol-4-yl) carbinol: ##STR1##

No pharmacological activity is ascribed to said compound.

In patent application EP 313 984, the bromo derivative: ##STR2## isdescribed as an intermediate for the synthesis of imidazole or triazolebased antifungal agents.

In patent application WO 91/08744, 4-hydroxythiazole derivatives areclaimed which are 5-lipoxygenase inhibitors. One example of suchcompounds is: ##STR3## 4-Oxygenated thiazoles are not included withinthe scope of the present invention.

In patent application EP 351 194 and in J. Med. Chem., 1991 34,2176-2186, compounds of the general formula: ##STR4## wherein Q isthiazolyl, Ar¹ is aryl of up to 10 carbon atoms, Ar² is 6-membered aryl,X is O, S, SO, SO₂ or NH and A is as direct link to X or is(1-6C)alkylene, (3-6C)alkenylene, (3-6C)alkynylene orcyclo(3-6C)alkylene are disclosed as 5-lipoxygenase inhibitors. Thesubstituent Ar¹ -A-X is not included within the scope of R¹ in claim 1of the present invention.

In patent application EP 390 558, imidazoles of the following generalstructure: ##STR5## are disclosed as aromatase inhibitors. Suchcompounds are deleted from the scope of the present invention by adisclaimer in claim 1.

In patent application EP 477 141, compounds of the general formula:##STR6## wherein Z is a five-membered aza-aromatic ring and X is cyano,carbamoyl or substituted carbamoyl are claimed. Said compounds arearomatase inhibitors. Specific examples are1-(4-cyanophenyl)-1-(5-thiazolyl)ethene and1-(4-cyanophenyl)-1-(5-thiazolyl)ethanol. Such substituents X are notincluded within the scope of the present invention.

In Tetrahedron, 1971, 27, 1211-1219 the compound1-(1,2-dimethyl-4-imidazolyl)-1-phenylethanol is described. Thiscompound is deleted from the scope of the present invention by adisclaimer in claim 1.

THE PRESENT INVENTION

A primary objective of the present invention is to provide structurallynovel heterocyclic compounds which by virtue of their pharmacologicalprofile are expected to be of value in the treatment of acute andchronic neuropsychiatric disorders characterised by progressiveprocesses that sooner or later lead to neuronal cell death anddysfunction. Such disorders include stroke; cerebral ischaemia;dysfunctions resulting from brain and/or spinal trauma; hypoxia andanoxia, such as from drowning, and including perinatal and neonatalhypoxic asphyxial brain damage; multi-infarct dementia; AIDS dementia;neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease, Huntington's chorea, epilepsy, multiple sclerosis andamytrophic lateral sclerosis; brain dysfunction in connection withsurgery involving extracorporeal circulation or in connection with brainsurgery, including endarterectomy of the carotid arteries; and CNSdysfunctions as a result of exposure to neurotoxins or radiation. Thisutility is manifested, for example, by the ability of these compounds toinhibit delayed neuronal death in the gerbil bilateral occlusion modelof ischaemia.

The present invention relates to a compound having the general formula(1) ##STR7## wherein: X is O, S, Se or NR₂ ;

R₁ is one or more groups selected from H, lower alkyl, lower acyl,halogen, lower alkoxy, CF₃, OH, NOhd 2 or NR₇ R₈ where R₇ and R₈independently are H, lower alkyl or lower acyl;

R₂ is H, lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkyl or CF₃; and when more than one R₂ groups are present these may be selectedindependently;

R₉ is H, lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkyl, CF₃ orNR₇ R₈ ;

and A is ##STR8## wherein W is O, S, NH or N-lower alkyl,

R₃ is H, lower alkyl or lower acyl,

R₄ is lower alkyl, aryl-lower alkyl or CF₃ ;

R₅ and R₆ independently are H, lower alkyl, or aryl-lower alkyl;

with the proviso that when X is N-H or N-(aryl-methyl), then A isneither ##STR9## and with the proviso that the following compound isexcluded: 1-(1,2-dimethyl-4-imidazolyl)-1-phenylethanol;

geometrical and optical isomers and racemates thereof where such isomersexist, as well as pharmaceutically acceptable acid addition saltsthereof and solvates thereof.

The expression "pharmaceutically acceptable acid addition salts" isintended to include but is not limited to such salts as thehydrochloride, hydrobromide, hydroiodide, nitrate, hydrogen sulphate,dihydrogen phosphate, ethanedisulphonate, mesylate, fumarate, maleateand succinate.

Preferred embodiments of this invention relate to compounds having thegeneral formula (2) ##STR10## wherein: X is O or S;

W is O;

and R₁, R₂, R₃, R₄ and R₉ are as previously defined above;

and to compounds having the general formula (3) ##STR11## wherein: X isO or S;

and R₁, R₂, R₅, R₆ and R₉ are as previously defined above.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all geometrical and optical isomers andracemates thereof where such isomers exist, as well as pharmaceuticallyacceptable acid addition salts thereof and solvates thereof such as forinstance hydrates.

The following definitions shall apply throughout the specification andthe appended claims.

Unless otherwise stated or indicated, the term "lower alkyl" denotes astraight or branched alkyl group having from 1 to 6 carbon atoms.Examples of said lower alkyl include methyl, ethyl, n-propyl, isopropyl,n-butyl, iso-butyl, t-butyl and straight- and branched-chain pentyl andhexyl.

Unless otherwise stated or indicated, the term "lower acyl" denotes astraight or branched acyl group having from 1 to 6 carbon atoms.Examples of said lower acyl include formyl, acetyl, propionyl,iso-butyryl, valeryl, and pivaloyl.

Unless otherwise stated or indicated, the term "lower alkoxy" denotes astraight or branched alkoxy group having from 1 to 6 carbon atoms.Examples of said lower alkoxy include methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight-andbranched-chain pentoxy and hexoxy.

Unless otherwise stated or indicated, the term "halogen " shall meanfluorine, chlorine, bromine or iodine.

Unless otherwise stated or indicated, the term "lower alkoxy-loweralkyl" denotes a lower alkyl group as defined above substituted by alower alkoxy group as defined above. Examples of said lower alkoxy-loweralkyl include methoxymethyl, ethoxymethyl, methoxyethyl and ethoxyethyl.

Unless otherwise stated or indicated, the term "aryl" denotes a phenyl,naphthyl, furyl, thienyl, pyridyl or pyrrolyl group, itself optionallysubstituted.

Unless otherwise stated or indicated, the term "aryl-lower alkyl"denotes a lower alkyl group as defined above substituted by an arylgroup as defined above. Examples of said aryl-lower alkyl includebenzyl, phenethyl, phenylpropyl, 4-fluorophenylmethyl, furfuryl,3-furylmethyl, tolylethyl and thienyl.

Among the most preferred compounds of formula (1) according to thepresent invention are:

1-(4-methyl-5-oxazolyl)-1-phenylethanol;

1-(4-methyl-5-thiazolyl)-1-phenylethanol;

1-(2-methoxyphenyl)-1-(4-methyl-5-oxazolyl)ethanol;

1-(4-methoxyphenyl)-1-(4-methyl-5-oxazolyl)ethanol;

1- (4-methyl-5-oxazolyl) -1- (2-trif luoromethyl-phenyl) - ethanol;

1-(4-methyl-5-thiazolyl)-1-phenylethene;

and pharmaceutically acceptable acid addition salts or solvates thereof.

The present invention also relates to processes for preparing thecompound having formula (1). Throughout the following generaldescription of such processes it is to be understood that, whereappropriate, suitable protecting groups will be added to, andsubsequently removed from, the various reactants and intermediates in amanner that will be readily understood by one skilled in the art oforganic synthesis. Conventional procedures for using such protectinggroups are described, for example, in "Protective Groups in organicSynthesis", T.W. Greene, Wiley-Interscience, New York, 1981.

Said compound wherein A is ##STR12## may be prepared by (a) reacting acompound of general formula (4) with an organometallic derivative ofgeneral formula (5) ##STR13## or (b) reacting a compound of generalformula (6) with an organometallic derivative of general formula (7)##STR14## or (c) reacting a compound of general formula (8) with anorganometallic derivative of general formula R₄ M ##STR15## andquenching the reaction mixture with a proton source (R₃ is H) or analkylating (R₃ is lower alkyl) or acylating (R₃ is lower acyl) reagent.Alternatively, the compound of formula (1)

wherein A is ##STR16## and R₃ is H may be first obtained as above andthen converted into the compound wherein R₃ is lower alkyl or loweracyl.

The processes (a), (b) or (c) can be achieved for example, by reactingtogether a ketone of structure (4 or (6) or (8) with a preformedorganometallic derivative (5) or (7) or R₄ M respectively in a suitableanhydrous solvent such as diethylether, tetrahydrofuran or hexane ormixtures thereof. Said reaction should be conducted at a suitabletemperature, normally between -100° C. and +50° C. and preferably underan inert atmosphere, normally nitrogen or argon. In a specificvariation, a solution of the ketone of structure (4) or (6) or (8) inanhydrous diethylether or tetrahydrofuran is added dropwise to theorganometallic derivative (5) or (7) or R₄ M respectively in anhydrousdiethylether or tetrahydrofuran or hexane or mixtures thereof at atemperature of about -50° C. to -78° C. and under an atmosphere ofnitrogen. After a suitable period of time the reaction mixture isallowed to warm to room temperature and then quenched by the addition ofwater or a lower alcohol. The required product (1) wherein A is##STR17## may then be isolated and purified and characterised usingstandard techniques.

Ketones of general formula (4) or (6) or (8) are either compounds whichare commercially available or have been previously described in theliterature, or compounds which can be prepared by the straightforwardapplication of known methods.

Thus, the present invention also refers to some new intermediates of thegeneral formulas (4) or (8), respectively, namely:

a compound of general formula (4) ##STR18## wherein X is O, S or Se;

R₄ is C₂ to C₆ alkyl;

and R₂ and R₉ are as defined in claim 1 with the proviso that thefollowing four compounds are excluded:

ethyl 4-thiazolyl ketone;

tert-butyl 5-thiazolyl ketone;

tert-butyl 5-oxazolyl ketone;

tert-butyl 4-tert-butyl-2-methyl-5-oxazolyl ketone;

or a compound of general formula (8) ##STR19## wherein X is O, S or Se;and R₁, R₂ and R₉ are as defined in claim 1, with the provisos that whenR₂ and R₉ are both H, then R₁ is not H or 4-Br; and that when R₉ is Hand R₂ is CH₃, then R₁ is not H or 4-OMe.

In the organometallic derivatives of general formula (5) or (7) or R₄ M,M represents a metallic residue such as Li or Mg-halogen. Such compoundsare either commercially available or have been previously described inthe literature, or can be prepared by the straightforward application ofknown methods of organometallic chemistry.

Compounds of formula (1) wherein A is ##STR20## may be prepared by (a)elimination of HWR3 from a compound of formula (1) wherein A is##STR21## or (b) by using a compound of general formula (8) as thesubstrate for a standard alkene forming reaction such as the Wittigreaction, the Peterson reaction or the McMurry reaction.

The process (a) can be achieved, for example, by treatment of a solutionof a compound of formula (1) wherein A is ##STR22## in a suitable inertsolvent with an acid or a base or a reagent such as thionyl chloride orphosphorus oxychloride. Said reaction should be conducted at a suitabletemperature, normally between -20° C. and the reflux temperature of thesolvent. In a preferred variation, a solution of a compound of formula(1) wherein A is ##STR23## in a solvent such as dichloromethane orchloroform at 0° C. to 10° C. is treated with an acid such as anhydroushydrogen chloride or p-toluenesulphonic acid, or with thionyl chloride.The reaction is then allowed to proceed at ambient temperature or above.The required product (1) wherein A is ##STR24## may then be isolated andpurified and characterised using standard techniques.

Compounds of formula (1) wherein A is ##STR25## may be prepared by (a)using a compound of general formula (1) wherein A is ##STR26## as thesubstrate for a Ritter reaction, or (b) by using a compound of generalformula (1) wherein A is ##STR27## as the substrate for a Mitsunobu-typereaction.

Some compounds of general formula (1) contain an asymmetric centre andcan thus exist in enantiomeric forms. These enantiomers may be separatedusing methods that will be well known to one skilled in the art. Suchmethods include, for example,

(i) direct separation by means of chiral chromatography, for example, byHPLC using a chiral column;

or (ii) recrystallisation of the diastereomeric salts formed by reactingthe base (1) with an optically active acid;

or (iii) derivatization of the compound of formula (1) by reaction withan optically active reagent, separation of the resultantdiastereoisomeric derivatives by, for example, crystallisation orchromatography, followed by regeneration of the compound of formula (1).

Alternatively, compounds of formula (1) may be obtained directly in anoptically active form by using a chemical or enzymatic based method ofasymmetric synthesis.

Some compounds of general formula (1) wherein A is ##STR28## can existas E and Z (trans and cis) isomers. Such isomers may be separated usingstandard techniques, for example, crystallisation or chromatography,that will be readily apparent to one skilled in the art.

PHARMACOLOGY

The neuroprotective properties of the compounds of formula (1) areexemplified by their ability to inhibit delayed neuronal death in thegerbil bilateral occlusion model of ischaemia.

Animals used were male Mongolian gerbils (60-80g). Drugs were dissolvedin isotonic saline containing dimethylsulphoxide.

Ischaemia was induced in the gerbils by 5 minute occlusion of bothcarotid arteries following the procedure described by R. Gill, A.C.Foster and G.N. Woodruff, J. Neuroscience. 1987, 7, 3343-3349. Bodytemperature was maintained at 37° C. throughout. Restoration of bloodflow after occlusion was checked visually and the animals were allowedto survive for 4 days. The extent of neuronal degeneration in thehippocampus was then assessed. The test compounds were administered(i.p.) as a single dose 60 minutes following occlusion. Noadministration was made prior to the occlusion. The effectiveness of thecompounds of formula (1) in decreasing damage to the CA1/CA2 hippocampalneurones in gerbils following ischaemic insult clearly illustrates theusefulness of these compounds in preventing neurodegeneration. Thesecompounds are therefore expected to be of value in the treatment ofacute and chronic neuropsychiatric disorders characterised byprogressive processes that sooner or later lead to neuronal cell deathand dysfunction.

PHARMACEUTICAL FORMULATIONS

The administration in the novel method of treatment of this inventionmay conveniently be oral, rectal, topical or parenteral at a dosagelevel of, for example, about 0.01 to 1000 mg/kg, preferably about 1.0 to500 mg/kg and especially about 5.0 to 200 mg/kg and may be administeredon a regimen of 1 to 4 doses or treatments per day. The dose will dependon the route of administration, preferred routes being oral orintravenous administration. It will be appreciated that the severity ofthe disease, the age of the patient and other factors normallyconsidered by the attending physician will influence the individualregimen and dosage most appropriate for a particular patient.

The pharmaceutical formulations comprising the compound of thisinvention may conveniently be tablets, pills, capsules, syrups, powdersor granules for oral administration; sterile parenteral solutions orsuspensions for parenteral administration; or as suppositories forrectal administration; or as suitable topical formulations. Conventionalprocedures for the selection and preparation of suitable pharmaceuticalformulations are described, for example, in "Pharmaceuticals - TheScience of Dosage Form Designs" , M. E. Aulton, Churchill Livingstone,1988.

To produce pharmaceutical formulations containing a compound accordingto the present invention in the form of dosage units for oralapplication the active substance may be admixed with an adjuvant/acarrier e.g. lactose, saccharose, sorbitol, mannitol, starches such aspotato starch, corn starch or amylopectin, cellulose derivatives, abinder such as gelatine or polyvinyl-pyrrolidone, and a lubricant suchas magnesium stearate, calcium stearate, polyethylene glycol, waxes,paraffin, and the like, and then compressed into tablets. If coatedtablets are required, the cores, prepared as described above, may becoated with a concentrated sugar solution which may contain e.g. gumarabic, gelatine, talcum, titanium dioxide, and the like. Alternatively,the tablet can be coated with a polymer known to the man skilled in theart, dissolved in a readily volatile organic solvent or mixture oforganic solvents. Dyestuffs may be added to these coatings in order toreadily distinguish between tablets containing different activesubstances or different amounts of the active compounds.

For the preparation of soft gelatine capsules, the active substance maybe admixed with e.g. a vegetable oil or polyethylene glycol. Hardgelatine capsules may contain granules of the active substance usingeither the above mentioned excipients for tablets e.g. lactose,saccharose, sorbitol, mannitol, starches (e.g. potato starch, cornstarch or amylopectin), cellulose derivatives or gelatine. Also liquidsor semisolids of the drug can be filled into hard gelatine capsules.

Dosage units for rectal application can be solutions or suspensions orcan be prepared in the form of suppositories comprising the activesubstance in admixture with a neutral fatty base, or gelatine rectalcapsules comprising the active substance in admixture with vegetable oilor paraffin oil.

Liquid preparations for oral application may be in the form of syrups orsuspensions, for example solutions containing from about 0.02% to about20% by weight of the active substance herein described, the balancebeing sugar and mixture of ethanol, water, glycerol and propyleneglycol. Optionally such liquid preparations may contain colouringagents, flavouring agents, saccharine and carboxymethylcellulose as athickening agent or other excipients known to the man in the art.

Solutions for parenteral applications by injection can be prepared in anaqueous solution of a water-soluble pharmaceutically acceptable salt ofthe active substance, preferably in a concentration of from about 0.5%to about 10% by weight. These solutions may also contain stabilizingagents and/or buffering agents and may involve the use of surface actingagents to improve solubility. They may conventiently be provided invarious dosage unit ampoules.

The necessary starting material for all Preparations and Examples werepurchased commercially except as follows:

4-methyl-5-oxazolecarbonyl chloride (Indian J. Chem., Sect. B., 1985,24B, 535-8);

5-acetyl-4-methyloxazole (Chem. Ber., 1960, 93, 1998-2001);

5-acetyl-4-methylthiazole (J. Agr. Food Chem., 1974, 22, 264-9);

5-acetyl-2,4-dimethyloxazole (Chem. Ber., 1960, 93, 1998-2001).

PREPARATION 1

N-Methoxy-N-methyl-4-methyl-5-oxazolecarboxamide

4-Methyl-5-oxazolecarbonyl chloride (15g) and N,O-dimethylhydroxylaminehydrochloride (11 g) in dry chloroform (looml) were cooled to OOC anddry pyridine (28.5g) was added. The mixture was allowed to warm to roomtemperature. After 30 minutes aqueous sodium hydrogen carbonate wasadded and the organic layer separated. The aqueous layer was extractedwith dichloromethane. The combined organic layers were washed, dried andevaporated. The residue was purified by flash chromatography to yieldthe title compound as a white solid. M.p. 59®-60° C. ¹ H Nmr (CDC₃) 2.5,3.34 and 3.82 (each 3H, s) and 7.86 (1H, S) ppm. Found: C, 49.0; H, 5.6;N, 16.4. C₇ H₁₀ N₂ O₃ requires C, 49.4; H, 5.9; N, 16.5%

PREPARATION 2

4-Methyl-5-oxazolyl Phenyl Ketone

Phenyllithium (1.8M solution in cyclohexane-diethylether, 11.7ml) in drytetrahydrofuran was stirred and cooled to -70° C. under an atmosphere ofdry nitrogen and N-methoxy-N-methyl-4-methyl-5-oxazolecarboxamide (3.0g)in dry tetrahydrofuran was added dropwise. After 30 minutes the mixturewas allowed to warm to room temperature. Ethanol (5ml) was addedfollowed by saturated aqueous sodium chloride. The mixture was extractedwith dichloromethane and the material thus obtained was purified byflash chromatography to give the title compound. M.p. 84-86° C. ¹ H Nmr(CDCl₃) 2.59 (3H, s), 7.5-7.68 (3H, m) and 7.96-8.06) (3H, m) ppm.

EXAMPLE 1

1-(4-Methyl-5-oxazolyl)-1-phenylethanol

5-Acetyl-4-methyloxazole (5g) in dry diethylether (25ml) at -70° C.under a nitrogen atmosphere was treated dropwise with phenyllithium(1.8M solution in cyclohexane-diethylether, 27ml). After 45 minutes themixture was allowed to warm to room temperature and water (10 ml) wasadded. The mixture was poured into saturated aqueous sodium chloride andextracted with dichloromethane. The product thus obtained wascrystallised from diethylether to give1-(4-methyl-5-oxazolyl)-1-phenylethanol, m.p. 102-104° C.

¹ H Nmr (CDC₃) 1.94 (3H, s), 2.0 (3H, s), 7.25-7.45 (5H, m) and 7.7 (1H,s) ppm.

¹³ C Nmr (CDC₃) 12.5, 29.7, 72.7, 125.1, 127.6, 128.4, 131.4, 145.2,148.6 and 149.8 ppm.

Found: C, 70.9; H, 6.6; N, 6.5. C₁₂ H₁₃ NO₂ requires C, 70.9; H, 6.45;N, 6.9%

EXAMPLE 2

1-(4-Methyl-5-thiazolyl)-1-phenylethanol

4-Methylthiazole (log) in dry tetrahydrofuran (50ml) at -70° C. wasstirred under a nitrogen atmosphere and n-butyllithium (2.5M solution inhexane, 44.4 ml) was added dropwise. After 30 minutes,trimethylsilylchloride (12.8 ml) was added and the reaction mixture wasallowed to warm to room temperature. After 30 minutes the mixture wascooled to -70° C. and n-butyllithium (44.4ml) was added dropwise. After30 minutes, acetophenone (12.9ml) was added dropwise and the mixturestirred at -70° C. for 1 hour. The reaction mixture was allowed to warmto room temperature and aqueous sodium hydrogen carbonate was added. Theorganic layer was separated and the aqueous layer was extracted withdiethylether. The combined organic layers were then worked up to affordthe title compound as a white solid, m.p. 128.5-129.5° C.

¹ H Nmr (CDCl₃) 2.01 and 2.1 (each 3H, s), 3.06 (1H, br s), 7.24-7.47(5H, m) and 8.5 (1H, s) ppm.

¹³ C Nmr (CDC₃) 16.2, 31.9, 73.7, 125.5, 127.6, 128.4, 139.7, 145.9,148.8 and 148.9 ppm.

Found: C, 65.6; H, 5.9; N, 6.3. C₁₂ H₁₃ NOS requires C, 65.7; H, 6.0; N,6.4%

Identical material was also obtained by the reaction of5-acetyl-4-methylthiazole with phenyllithium according to the generalmethod of Example 1.

EXAMPLE 3

1-(2-Methoxyphenyl)-1-(4-methyl-5-oxazolyl)ethanol

2-Bromoanisole (4.86g) in anhydrous diethylether (10 ml) was addeddropwise to a stirred solution of n-butyllithium (2.5M solution inhexane, 10.4 ml) in diethylether (30 ml) at -70° C. under an atmosphereof dry nitrogen. After 45 minutes, 5-acetyl-4-methyloxazole (2.5g) indiethylether (loml) was added dropwise. After a further 1 hour at -70°C. the reaction mixture was allowed to warm to room temperature and wasstirred overnight. Saturated aqueous sodium hydrogen carbonate wasadded. The organic layer was separated and the aqueous layer wasextracted with diethylether. The combined organic layers were furtherprocessed to give the title compound as a white solid, m.p. 74-75° C.

¹ H Nmr (CDCl₃) 1.92, 2.0 and 3.78 (each 3H, s), 4.61 (lH, s), 6.92 (1H,d), 7.0 (1H, t), 7.26-7.37 (2H, m) and 7.64 (1H, s) ppm.

¹³ C Nmr (CDC₃) 12.1, 27.0, 55.6, 72.3, 111.5, 121.1, 126.6, 129.3,130.2, 132.4, 148.0, 149.8 and 156.9 ppm.

Found: C, 66.8; H, 6.7; N, 6.05. C₁₃ H₁₅ NO₃ requires C, 66.9; H, 6.5;N, 6.0%

EXAMPLE 4

1-(4-Methoxvphenyl)-1-(4-methyl-5-oxazolyl)ethanol

Following the general method of Example 3 but starting with4-bromoanisole, the title compound was prepared.

M.p. 115-116° C.

¹ H Nmr (CDC₃) 1.9, 1.98 and 3.8 (each 3H, s), 3.07 (1H, s), 6.87 (1H,d), 7.33 (1H, d) and 7.65 (1H, s) ppm.

¹³ C Nmr (CDCl₃) 12.4, 29.7, 55.2, 72.3, 113.7, 126.4, 131.1, 137.5,148.5, 150.0 and 159.0 ppm.

Found: C, 67.1; H, 6.5; N, 6.1. C₁₃ H₁₅ NO₃ requires C, 66.9; H, 6.5; N,6.0%

EXAMPLE 5

1-(4-Methyl-5-oxazolyl)-1-(2-trifluoromethylphenyl)- ethanol

Following the general method of Example 3 but starting with2-trifluoromethylbromobenzene, the title compound was prepared.

M.p. 108-109° C.

¹ H Nmr (CDC₃) 1.95 and 2.02 (each 3H, s), 2.59 (1H, s), 7.43 and 7.56(each 1H, t), 7.7 (1H, s) and 7.73-7.78 (2H, m) ppm.

Found: C, 57.3; H, 4.3; N, 5.1. C₁₃ H₁₂ F₃ NO₂ requires C, 57.6; H, 4.5;N, 5.2%

Treatment of the above product with anhydrous hydrogen chloride indiethylether gave 1-(4-methyl-5-oxazolyl)-1-(2-trifluoromethylphenyl)ethanol hydrochloride as a white solid, m.p. 104-105° C.

Found: C, 50.6; H, 4.1; N, 4.5. C₁₃ H₁₂ F₃ NO₂ ·HCl requires C, 50.7; H,4.3; N, 4.55%

EXAMPLE 6

1-(4-Methyl-5-thiazolyl)-1-phenylethene

1-(4-Methyl-5-thiazolyl)-1-phenylethanol (2.5g) in chloroform (25ml) wastreated with thionyl chloride (4.5ml). The mixture was heated underreflux overnight and then evaporated to dryness. Aqueous sodium hydrogencarbonate was added and the mixture was extracted with dichloromethane.The material thus obtained was purified by flash chromatography to givethe title compound as an oil. Treatment with anhydrous hydrogen chloridein diethylether gave 1-(4-methyl-5-thiazolyl) -1-phenylethenehydrochloride, m.p. 131-133.5° C.

1H Nmr (d₆ -DMSO) 1.85 (3H, s), 5.15 and 5.52 (each 1H, s), 6.96-7.07(SH, m) and 8.82 (1H, s) ppm.

¹³ C Nmr (d₆ -DMSO) 15.4, 119.2, 126.6, 128.3, 128.5, 131.2, 138.8,139.4, 148.7 and 152.4 ppm.

Found: C, 60.6; H, 5.0; N, 5.7. C₁₂ H₁₁ NS·HCl requires C, 60.6; H, 5.1;N, 5.9%

EXAMPLE 7

1- (4-Methyl) -5-oxazolyl) -1- (4-trifluoromethylphenyl)-ethanol

Following the general method of Example 3 but starting with4-trifluoromethylbromobenzene, the title compound was prepared.

M.p. 89-91° C.

¹ H Nmr (CDCl₃) 1.93 and 2.01 (each 3H, s), 3.18 (1H, s), 7.54 and 7.62(each 2H, d) amd 7.7 (1H, s) ppm.

The corresponding hydrochloride salt was prepared, m.p. 110-111° C.

EXAMPLE 8

1-(4-Methoxyphenyl)-1-(2,4-dimethyl-5-thiazolvl)ethanol

Following the general method of Example 3 but starting with4-bromoanisole and 5-acetyl-2,4-dimethylthiazole, the title compound wasprepared. M.p. 114-115.5° C.

¹³ C Nmr (CDC₃) 16.2, 18.8, 31.9, 55.2, 73.5, 113.6, 126.8, 138.5,139.2, 147.6, 159.2 and 162.3 ppm.

EXAMPLE 9

1-(4-Methyl-5-thiazolyl) -1-phenyl-2,2,2-trifluoroethanol

Following the general method of Example 2 but starting with2,2,2-trifluoroacetophenone, the title compound was prepared.

M.p. 180-181.5° C.

¹ H Nmr (d₆ -DMSO) 1.6 (3H, s), 7.1 (5H, m) and 8.66 (1H, s) ppm.

EXAMPLE 10

1-(4-Methoxyphenyl)-1-(2,4-dimethyl-5-thiazolyl)ethene

1- (4-Methoxyphenyl) -1- (2, 4-dimethyl-5-thiazolyl) ethanol (3.69g) inchloroform (50ml) was treated with hydrogen chloride in dry diethylether (1M, 14.5ml). After 2 hours at room temperature, aqueous sodiumhydrogen carbonate was added and the mixture was extracted withchloroform. The material thus obtained was purified by flashchromatography to yield the title compound.

¹ H Nmr (CDC1₃) 2.2, 2.65 and 3.83 (each 3H, s), 5.27 and 5.60 (each 1H,s), and 6.86 and 7.28 (each 2H, d) ppm.

Hydrochloride, m.p. 139-140° C. ¹³ C Nmr (d₆ -DMSO) 15.1, 17.9, 55.1,113.9, 117.1, 128.0, 131.0, 131.7, 138.0, 146.5, 159.4 and 164.3 ppm.

EXAMPLE 11

1-(2,4-Dimethyl-5-thiazolyl)-1-phenylethanol

The title compound was prepared following the general method of Example1 but starting with 5-acetyl-2,4-dimethylthiazole.

M.p. 131-132° C. ¹³ C Nmr (CDC₃) 16.2, 18.7, 32.3, 73.6, 125.4, 127.4,128.3, 138.8, 146.4, 147.6 and 161.8 ppm.

EXAMPLE 12

1-(2,4-Dimethyl-5-oxazolyl)-1-phenylethanol

The title compound was prepared following the general method of Example1 but starting with 5-acetyl-2,4-dimethyloxazole.

M.p. 94.5-96° C. ¹³ C Nmr (CDC₃) 12.3, 13.6, 29.8, 72.5, 125.1, 127.4,128.2, 131.4, 145.6, 149.2 and 158.9 ppm.

EXAMPLE 13

1-Phenyl-1-(5-thiazolyl)ethanol

n-Butyllithium (2.5M solution in hexane, 7ml) in diethyl ether (30ml)was stirred at -70° C. under a nitrogen atmosphere and2-trimethylsilylthiazole (2.5g) in diethyl ether (10 ml) was addeddropwise. After 30 minutes, acetophenone (2.3g) in diethyl ether (10 ml)was added dropwise. After a further 45 minutes the mixture was allowedto warm to room temperature and was then left overnight. Water was addedand the mixture was extracted with diethyl ether. The material thusobtained was purified by flash chromatography to give the titlecompound.

M.p. 86-87° C. ¹³ C Nmr (CDC₃) 32.2, 73.3, 125.1, 127.5, 128.3, 139.4,146.5, 148.6 and 153.1 ppm.

We claim:
 1. A compound having the general formula (1) ##STR29##wherein: X is O, S, or Se;R₁ is one or more groups selected from H,lower alkyl, lower acyl, halogen, lower alkoxy, CF₃, OH, NO₂ or NR₇ R₈where R₇ and R₈ independently are H, lower alkyl or lower acyl; R₂ is H,lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkyl or CF₃ ; R₉ isH, lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkyl, CF₃ or NR₇R₈ ; and A is ##STR30## wherein W is O, S, NH or N-lower alkyl; R₃ is H,lower alkyl or lower acyl; R₄ is lower aklyl, aryl-lower alkyl or lowerperfluoroalkyl; R₅ and R₆ independently are H, lower alkyl, oraryl-lower alkyl;geometric and optical isomers and racemates thereofwhere such isomers exist, as well as pharmaceutically acceptable acidaddition salts thereof and solvates thereof.
 2. A compound according toclaim 1 having the general formula (2) ##STR31## wherein: X is O or S;Wis O and R₁, R₂, R₃, R₄ and R₉ are as defined in claim
 1. 3. A compoundaccording to claim 1 having the general formula (3) ##STR32## wherein: Xis O or S;and R₁, R₂, R₅, R₆ and R₉ are as defined in claim
 1. 4. Acompound according to claim 1 selected from the group consistingof1-(4-methyl-5-oxazolyl)-1-phenylethanol;1-(4-methyl-5-thiazolyl)-1-phenylethanol;1-(2-methoxyphenyl)-1-(4-methyl-5-oxazolyl)ethanol;1-(4-methoxyphenyl)-1-(4-methyl-5-oxazolyl)ethanol; 1-(4-methyl-5-oxazolyl) -1- (2-trifluoromethyl-phenyl) -ethanol;1-(4-methyl-5-thiazolyl)-1-phenylethene;and pharmaceutically acceptableacid addition salts or solvates thereof.
 5. A pharmaceutical formulationcontaining a compound having the general formula (1) ##STR33## wherein:X is O, S, or Se,;R₁ is one or more groups selected from H, lower alkyl,lower acyl, halogen, lower alkoxy, CF₃, OH, NO₂ or NR₇ R₈ where R₇ andR₈ independently are H, lower alkyl or lower acyl; R₂ is H, lower alkyl,lower alkoxy-lower alkyl, aryl-lower alkyl or CF₃ and when more than oneR₂ groups are present these may be selected independently; R₉ is H,lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkyl, CF₃ or NR₇ R₈ ;and A is ##STR34## wherein W is O, S, NH or N-lower alkyl; R₃ is H,lower alkyl or lower acyl; R₄ is lower alkyl, aryl-lower alkyl or CF₃ ;R₅ and R₆ independently are H, lower alkyl, or aryl-loweralkyl;geometric and optical isomers and racemates thereof where suchisomers exist, as well as pharmaceutically acceptable acid additionsalts thereof and solvates thereof, as active ingredient and apharmaceutically acceptable carrier.
 6. A compound as defined in claim 1for the treatment of stroke; cerebral ischaemia; dysfunctions resultingfrom brain and/or spinal trauma; hypoxia and anoxia; multi-infarctdementia; AIDS dementia; neurodegenerative diseases; brain dysfunctionin connection with surgery; and CNS dysfunctions as a result of exposureto neurotoxins or radiation.
 7. A method for the treatment of acute andchronic neuropsychiatric disorders characterised by progressiveprocesses that lead to neuronal cell death and dysfunction comprisingadministering to a host in need of such treatment a sufficient amount ofa compound having the formula (1) ##STR35## wherein: X is O, S, Se, orNR2;R₁ is one or more groups selected from H, lower alkyl, lower acyl,halogen, lower alkoxy, CF₃, OH, NO₂ or NR₇ R₈ where R₇ and R₈independently are H, lower alkyl or lower acyl; R₂ is H, lower alkyl,lower alkoxy-lower alkyl, aryl-lower alkyl or CF₃ and when more than oneR₂ groups are present these may be selected independently; R₉ is H,lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkyl, CF₃ or NR₇ R₈;and A is ##STR36## wherein W is O, S, NH or N-lower alkyl; R₃ is H,lower alkyl or lower acyl; R₄ is lower alkyl, aryl-lower alkyl or CF₃ ;R₅ and R₆ independently are H, lower alkyl, or aryl-lower alkyl;with theproviso that when X is N-H or N-(aryl-methyl), then A is neither##STR37## geometric and optical isomers and racemates thereof where suchisomers exist, as well as pharmaceutically acceptable acid additionsalts thereof and solvates thereof.